Hyperpolarized xenon-129 (HXe) MRI is poised to address critical areas of unmet need. Toward advancement of more personalized medicine, researchers are validating pulmonary applications in disease diagnosis, severity staging, managing treatments, and evaluating outcomes. In support of drug development trials, researchers are validating precise imaging biomarkers for regional ventilation, alveolar dimension, oxygen uptake, collateral pathways, the ratio of parenchyma volume to alveolar gas volume, septal wall thickness, and gas exchange to red blood cells. A suite of new xenon polarizer technologies is largely responsible for this surge in research activity. Our UNH team originated the production of hyperpolarized xenon in the high-flow low-pressure regime by inventing the counter-flow polarization process. Subsequent inventions included cryogenic separation of hyperpolarized xenon from flowing gases using a rising dewar, spectral narrowing of diode laser stacks using a stepped- mirror, and scale up of production output using a multi-channel copper column. These technologies were combined in a prototype polarizer that produced batches of two liters of 30% polarized xenon for 600 human subject experiments over a four month period. This success impressive though it may be, nevertheless fell short of the calculated potential of the technique: the factor of five improvement in production output did not reach the factor of fourteen increase in the polarizer column cross-section. The 30% polarization delivered in the clinic is well below the potential maximum of over 80%. The freeze-out separation that we had validated in the lab, suffered inconsistencies and occasional failures in the clinic, reducing both the quantity of gas recovered as well as its polarization. We propose a program of technological innovations, diagnostic tests, and analytical evaluations to support another factor of three-to-five improvement in xenon polarizer output. To increase optical pumping efficiency we will test Rb-Cs alkali mix for hybrid pumping. To address the unexplained drop in polarization coming from the column we will evaluate performance improvements achieved by attaching a thin aluminosilicate coating to the copper. To prevent partial (or total) losses of xenon snow being blown from the freeze-out, we will introduce a fine tungsten wire coil into the helixes to anchor the snow while thawing. To accelerate thawing we will evaluate operational scenarios for a diaphragm pump to control the xenon pressure. The recent recognition that 3He supplies are highly oversubscribed focuses greater emphasis on validating HXe for regulatory approval and commercialization as an agent for pulmonary functional imaging. Approval of this proposal would provide the only support to the leading xenon polarization academic group to continue making fundamental advances to the science and technology underpinning this field. PUBLIC HEALTH RELEVANCE: Hyperpolarized xenon-129 (HXe) MRI is poised to address critical areas of need in pulmonary functional imaging, both as an imaging modality for managing patients as well as a drug development tool for pharmaceutical trials. A series of new technological breakthroughs in polarizer technology have recently enabled a surge in research, however our measurements and calculations indicate a vast untapped potential of performance improvements can still be accessed. We propose to implement several new technologies in order to gain an additional factor of three-to-five improvement in polarization and output, and improved consistency and reliability.